Abstract
Very little is known to which extent severe underweight could affect cytochrome P‐450 (CYP) enzyme activity. In this study, 24 patients with anorexia nervosa at two occasions ingested single oral doses of five test drugs known to be metabolized by CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively. A mixed model analysis was used to evaluate the effect of changes in body mass index (BMI) on the metabolic activities of these enzymes. The primary end point was the change in drug/metabolite ratio of each of the test drugs per kg/m2 change in BMI. With increasing BMI, the metabolic activity of CYP3A4 decreased (change in the CYP3A4 drug/metabolite ratio per unit change in BMI = 0.056; 95% confidence interval [CI] 0.011 to 0.102; P = .017). For CYP1A2, increasing BMI increased the metabolic activity with borderline significance (change in the CYP1A2 drug/metabolite ratio per unit change in BMI = –0.107; CI –0.220 to 0.005; P = .059). For CYP2C9, CYP2C19, and CYP2D6, no significant changes were seen. The clinical impact of these findings for drug treatment in patients with anorexia nervosa and other severely underweight patients needs to be further studied by examining the pharmacokinetics of specific drugs. This might be particularly relevant for drugs metabolized by CYP1A2 and/or CYP3A4.
Highlights
About 80% of currently used medicines are metabolized by cytochrome P-450 (CYP) enzymes.[1,2] If the activity of these enzymes is altered related to changes in body weight or nutritional state, the plasma concentration of relevant drugs will be affected
Due to the lack of information on the possible effect of low body weight on most CYP enzymes, the aim of this study was to explore whether changes in body weight in patients with anorexia nervosa affect the metabolic activity of the CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4
The caffeine/paraxanthine ratio was calculated as a measure of CYP1A2 activity, the losartan/EXP-3174 ratio was calculated as a measure of CYP2C9 activity, the omeprazole/5-OH-omeprazole ratio was calculated as a measure of CYP2C19 activity, the dextromethorphan/dextrorphan ratio was calculated as a measure of CYP2D6 activity and the quinine/3-hydroxyquinine ratio was calculated as a measure of CYP3A4 activity
Summary
About 80% of currently used medicines are metabolized by cytochrome P-450 (CYP) enzymes.[1,2] If the activity of these enzymes is altered related to changes in body weight or nutritional state, the plasma concentration of relevant drugs will be affected. About 80% of currently used medicines are metabolized by cytochrome P-450 (CYP) enzymes.[1,2]. If the activity of these enzymes is altered related to changes in body weight or nutritional state, the plasma concentration of relevant drugs will be affected. The major CYP enzymes involved in drug metabolism include CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.1. For CYP1A2, CYP2C9, CYP2C19, and CYP2D6, there are no studies on enzyme activities in anorexia nervosa or otherwise underweight subjects. The effects of obesity on CYP enzyme activities have been widely studied (for a review, see 3).
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